This is an effort to relate polymorphisms in DNA repair to incidence of breast cancer. Mutations in both the BER and HRR pathways are proposed to make an individual more sensitive to ionizing radiation and breast cancer. Assays for assessing decreased activity in these pathways will also be pursued. Our long-term goal in cancer prevention is to identify high-risk populations by using DNA repair markers and to design mechanistic-based prevention strategy tailored to the specific risk profiles of individuals. Human cells are constantly exposed to exogenous and endogenous carcinogens capable of causing DNA damage. Efficient repair is critical in maintaining genome integrity and genetic variability in DNA repair may influence individual's susceptibility to cancer. Our working hypothesis is that polymorphism of DNA repair genes with nonconservative amino acid substitution may lead to altered protein function in DNA repair and elevated breast cancer risk. Various man-made therapeutic, diagnostic, or occupational exposure to ionizing radiation have been linked to human breast cancer risk. The variety of DNA lesions induced by IR are mainly repaired by base excision repair (BER) and homologous recombinational repair (HRR). Data from our pilot study support the hypothesis that polymorphisms of genes in BER and HRR may be associated with hypersensitivity to ionizing radiation and susceptibility to breast cancer. To achieve our long-term goal, the primary objective of this study is to characterize DNA repair genotype and phenotype in breast cancer risk assessment. The secondary objective is to develop more specific activity assays for BER and HRR in order to evaluate the functional significance of individual DNA repair genetic variant in response to IR. This study will use existing genomic DNA, cryopreserved lymphocytes, and questionnaire data collected in an ongoing NCI-funded (CA73629) breast cancer case-control study. The study subjects will include 200 newly diagnosed, untreated breast cancer cases and 200 controls (frequency-matched to cases on race and age [equal to or less than 5 yrs]) recruited from Wake Forest University Baptist Medical Center. A questionnaire was use to collect information on established breast cancer risk factors. This proposed research is exceptionally cost-effective and efficient since the most costly tasks (e.g., recruitment and collection of samples and data) are supported by the parent study. Viable lymphocytes will provide an extremely unique opportunity to investigate the functional significance of DNA repair variants, which is crucial in evaluating the usefulness of SNPs of DNA repair genes as susceptibility markers.